TREPULMIX 10mg / ml infusion solution medication leaflet

Trepulmix 1 mg/ml solution for infusion

Trepulmix 2.5 mg/ml solution for infusion

Trepulmix 5 mg/ml solution for infusion

Trepulmix 10 mg/ml solution for infusion

Trepulmix 1 mg/ml solution for infusion

One ml of solution contains 1 mg treprostinil (as sodium salt).

Each 10 ml vial of solution contains 10 mg treprostinil (as sodium salt).

Each 10 ml vial contains 36.8 mg (1.60 mmol) sodium.

Trepulmix 2.5 mg/ml solution for infusion

One ml of solution contains 2.5 mg treprostinil (as sodium salt).

Each 10 ml vial of solution contains 25 mg treprostinil (as sodium salt).

Each 10 ml vial contains 37.3 mg (1.62 mmol) sodium.

Trepulmix 5 mg/ml solution for infusion

One ml of solution contains 5 mg treprostinil (as sodium salt).

Each 10 ml vial of solution contains 50 mg treprostinil (as sodium salt).

Each 10 ml vial contains 39.1 mg (1.70 mmol) sodium.

Trepulmix 10 mg/ml solution for infusion

One ml of solution contains 10 mg treprostinil (as sodium salt).

Each 10 ml vial of solution contains 100 mg treprostinil (as sodium salt).

Each 10 ml vial contains 37.4 mg (1.63 mmol) sodium.

For the full list of excipients, see section 6.1.

Solution for infusion.

Clear colourless to slightly yellow solution, free from visible particles with a pH of 6.0 - 7.2 and anosmolality between 253 and 284 mOsm/kg.

Trepulmix is indicated for the treatment of adult patients with WHO Functional Class (FC) III or IVand:

- inoperable chronic thromboembolic pulmonary hypertension (CTEPH), or

- persistent or recurrent CTEPH after surgical treatment to improve exercise capacity.

Treatment with Trepulmix should be initiated and monitored only by clinicians experienced in thetreatment of pulmonary hypertension. Treatment should be initiated under close medical supervision ina medical setting able to provide intensive care.

The recommended initial infusion rate is 1.25 ng/kg/min. If this initial dose is poorly tolerated, theinfusion rate should be reduced to 0.625 ng/kg/min.

The infusion rate should be increased under medical supervision in increments of up to 1.25 ng/kg/minper week for the first four weeks of treatment and then up to 2.5 ng/kg/min per week.

The dose should be adjusted on an individual basis and under medical supervision in order to achieve amaintenance dose at which symptoms improve and which is tolerated by the patient.

During the follow-up phase of a clinical trial in CTEPH patients, the mean doses reached after 12months were 31 ng/kg/min, after 24 months 33 ng/kg/min, and after 48 months 39 ng/kg/min. Therespective maximum doses observed in the clinical trial were 52 ng/kg/min, 54 ng/kg/min and50 ng/kg/min respectively.

Abrupt withdrawal or sudden marked reductions in the dose of treprostinil may cause a rebound ofsymptoms of chronic thromboembolic pulmonary hypertension. It is therefore recommended thatinterruption of treprostinil therapy is avoided and that the infusion is re-started as soon as possibleafter an abrupt accidental dose reduction or interruption. The optimal strategy for reintroducingtreprostinil infusion needs to be determined on a case by case basis by medically qualified personnel.

In most cases, after an interruption of up to 4 hours, restarting of treprostinil infusion can be doneusing the same dose rate; interruptions for up to 24 hours may require a dose reduction of up to 50% ofthe most recent dose with a subsequent uptitration to the clinically effective dose. Longer periods ofinterruption may require the dose of treprostinil to be re-titrated from even lower flow rates. In anycase, the reintroduction of treprostinil should be under medical supervision.

The initial dose of Trepulmix should be decreased to 0.625 ng/kg/min and incremental dose increasesshould be made cautiously (see section 5.2). Increments could be reduced to 0.625 ng/kg/min per doseincrease, the final decision on the dose increments is at the discretion of the supervising physician.

Please note that severe hepatic impairment (Child-Pugh Class C) is listed as contraindication for use oftreprostinil, see section 4.3.

As no clinical studies have been carried out in patients with renal impairment, the treatmentrecommendations are not established for patients with renal impairment. As treprostinil and itsmetabolites are excreted mainly through the urinary route, caution is recommended when treatingpatients with renal impairment in order to prevent deleterious consequences related to the possibleincrease of systemic exposure.

No pharmacokinetic data of treprostinil in elderly is available. Caution is recommended when treatingelderly patients due to higher incidence of hepatic and/or renal impairment.

Obese patients

Therapy of obese patients (weight ≥ 30% above ideal weight) should be initiated and increased withdoses calculated based on their ideal weight. See section 5.2 for more information.

There is no relevant use of treprostinil in children and adolescents for the indication of CTEPH.

Trepulmix is for subcutaneous use. It is administered undiluted by continuous infusion via asubcutaneous catheter using an ambulatory infusion pump.

The healthcare professional responsible for the therapy must ensure that the patient is fully trained andcompetent to use the chosen infusion device. All patients must be trained in preparation of thetreprostinil infusion reservoir and priming of the infusion delivery tubing and connection. Writtenguidance, either from the pump manufacturer or specially tailored advice by the prescribing physicianmust be made available to the patient. This includes the required normal drug delivery actions, advicehow to manage occlusions and other pump alarms, and details whom to contact in an emergency.

In order to avoid interruptions in drug delivery, the patient must have access to a backup infusionpump and subcutaneous infusion sets in the event that the administration equipment should suffer anaccidental malfunction.

The ambulatory infusion pump used to administer undiluted Trepulmix subcutaneously, should be:

* small and lightweight,

* capable of adjusting infusion rates in increments of 0.002 ml/h or less,

* fitted with occlusion, low battery, programming error and motor malfunction alarms,

* accurate to within +/- 6% of the programmed delivery rate

* positive pressure driven (continuous or pulsated).

The reservoir must be made of polypropylene or glass.

Patients must be thoroughly trained in the use and programming of the pump, and the connection andcare of the infusion set.

Flushing the infusion line whilst connected to the patient may lead to accidental overdose. For moreinformation on the symptoms and treatment of overdose please refer to Section 4.9 of this document.

Trepulmix is available at concentrations of 1, 2.5, 5 and 10 mg/ml.

For subcutaneous infusion, Trepulmix is delivered without further dilution at a calculatedsubcutaneous infusion rate (ml/h) based on a patient’s dose (ng/kg/min), weight (kg), and the vialstrength (mg/ml) of Trepulmix being used. During use a single reservoir (syringe) of undiluted

Trepulmix can be administered up to 72 hours at 37 °C. The subcutaneous infusion rate is calculatedusing the following formula:

Subcutaneous Dose (ng/kg/min) x Weight (kg) x 0.00006*infusion rate =(ml/h) Trepulmix vial strength (mg/ml)

*Conversion factor of 0.00006 = 60 min/hour x 0.000001 mg/ng

To avoid calculation errors due to the complex formula please check the dose calculation tablesbelow. For each medicinal product strength one dose calculation table is available.

Example calculations for subcutaneous infusion are as follows:

Example 1:

For a 60 kg person at the recommended initial dose of 1.25 ng/kg/min using the 1 mg/ml Trepulmix vialstrength, the infusion rate would be calculated as follows:

Subcutaneousinfusion rate = 1.25 ng/kg/min x 60 kg x 0.00006(ml/h) 1 mg/ml = 0.005 ml/h

Example 2:

For a 65 kg person at a dose of 40 ng/kg/min using the 5 mg/ml Trepulmix vial strength, the infusionrate would be calculated as follows:

Subcutaneous 40 ng/kg/min x 65 kg x 0.00006infusion rate = 5 mg/ml = 0.031 ml/h(ml/h)

Table 1-1 provides guidance for subcutaneous infusion delivery rates of Trepulmix 1 mg/ml forpatients of different body weights corresponding to doses of up to 42.5 ng/kg/min.

Table 1-1:

Infusion rate setting of subcutaneous pump (ml/h) for Trepulmix 1 mg/ml

Patient weight (kg)

Dose(ng/kg/min) 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 1001.25 0.002 0.002 0.003 0.003 0.003 0.004 0.004 0.005 0.005 0.005 0.006 0.006 0.006 0.007 0.007 0.0082.5 0.004 0.005 0.005 0.006 0.007 0.008 0.008 0.009 0.010 0.011 0.011 0.012 0.013 0.014 0.014 0.0153.75 0.006 0.007 0.008 0.009 0.010 0.011 0.012 0.014 0.015 0.016 0.017 0.018 0.019 0.020 0.021 0.0235 0.008 0.009 0.011 0.012 0.014 0.015 0.017 0.018 0.020 0.021 0.023 0.024 0.026 0.027 0.029 0.0306.25 0.009 0.011 0.013 0.015 0.017 0.019 0.021 0.023 0.024 0.026 0.028 0.030 0.032 0.034 0.036 0.0387.5 0.011 0.014 0.016 0.018 0.020 0.023 0.025 0.027 0.029 0.032 0.034 0.036 0.038 0.041 0.043 0.0458.75 0.013 0.016 0.018 0.021 0.024 0.026 0.029 0.032 0.034 0.037 0.039 0.042 0.045 0.047 0.050 0.05310 0.015 0.018 0.021 0.024 0.027 0.030 0.033 0.036 0.039 0.042 0.045 0.048 0.051 0.054 0.057 0.06011.25 0.017 0.020 0.024 0.027 0.030 0.034 0.037 0.041 0.044 0.047 0.051 0.054 0.057 0.061 0.064 0.06812.5 0.019 0.023 0.026 0.030 0.034 0.038 0.041 0.045 0.049 0.053 0.056 0.060 0.064 0.068 0.071 0.07513.75 0.021 0.025 0.029 0.033 0.037 0.041 0.045 0.050 0.054 0.058 0.062 0.066 0.070 0.074 0.078 0.08315 0.023 0.027 0.032 0.036 0.041 0.045 0.050 0.054 0.059 0.063 0.068 0.072 0.077 0.081 0.086 0.09016.25 0.024 0.029 0.034 0.039 0.044 0.049 0.054 0.059 0.063 0.068 0.073 0.078 0.083 0.088 0.093 0.09817.5 0.026 0.032 0.037 0.042 0.047 0.053 0.058 0.063 0.068 0.074 0.079 0.084 0.089 0.095 0.100 0.10518.75 0.028 0.034 0.039 0.045 0.051 0.056 0.062 0.068 0.073 0.079 0.084 0.090 0.096 0.101 0.107 0.11320 0.030 0.036 0.042 0.048 0.054 0.060 0.066 0.072 0.078 0.084 0.090 0.096 0.102 0.108 0.114 0.12021.25 0.032 0.038 0.045 0.051 0.057 0.064 0.070 0.077 0.083 0.089 0.096 0.102 0.108 0.115 0.121 0.12822.5 0.034 0.041 0.047 0.054 0.061 0.068 0.074 0.081 0.088 0.095 0.101 0.108 0.115 0.122 0.128 0.13523.75 0.036 0.043 0.050 0.057 0.064 0.071 0.078 0.086 0.093 0.100 0.107 0.114 0.121 0.128 0.135 0.14325 0.038 0.045 0.053 0.060 0.068 0.075 0.083 0.090 0.098 0.105 0.113 0.120 0.128 0.135 0.143 0.15027.5 0.041 0.050 0.058 0.066 0.074 0.083 0.091 0.099 0.107 0.116 0.124 0.132 0.140 0.149 0.157 0.16530 0.045 0.054 0.063 0.072 0.081 0.090 0.099 0.108 0.117 0.126 0.135 0.144 0.153 0.162 0.171 0.18032.5 0.049 0.059 0.068 0.078 0.088 0.098 0.107 0.117 0.127 0.137 0.146 0.156 0.166 0.176 0.185 0.19535 0.053 0.063 0.074 0.084 0.095 0.105 0.116 0.126 0.137 0.147 0.158 0.168 0.179 0.189 0.200 0.21037.5 0.056 0.068 0.079 0.090 0.101 0.113 0.124 0.135 0.147 0.158 0.169 0.180 0.191 0.203 0.214 0.22540 0.060 0.072 0.084 0.096 0.108 0.120 0.132 0.144 0.156 0.168 0.180 0.192 0.204 0.216 0.228 0.24042.5 0.064 0.077 0.089 0.102 0.115 0.128 0.140 0.153 0.166 0.179 0.191 0.204 0.217 0.230 0.242 0.255

The shaded areas indicate the highest infusion rate which is possible with a 3 ml syringe change everythree days.

Table 1-2 provides guidance for subcutaneous infusion delivery rates of Trepulmix 2.5 mg/ml forpatients of different body weights corresponding to doses of up to 42.5 ng/kg/min.

Table 1-2:

Infusion rate setting of subcutaneous pump (ml/h) for Trepulmix 2.5 mg/ml

Patient weight (kg)

Dose(ng/kg/min) 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 1005 0.003 0.004 0.004 0.005 0.005 0.006 0.007 0.007 0.008 0.008 0.009 0.010 0.010 0.011 0.011 0.0126.25 0.004 0.005 0.005 0.006 0.007 0.008 0.008 0.009 0.010 0.011 0.011 0.012 0.013 0.014 0.014 0.0157.5 0.005 0.005 0.006 0.007 0.008 0.009 0.010 0.011 0.012 0.013 0.014 0.014 0.015 0.016 0.017 0.0188.75 0.005 0.006 0.007 0.008 0.009 0.011 0.012 0.013 0.014 0.015 0.016 0.017 0.018 0.019 0.020 0.02110 0.006 0.007 0.008 0.010 0.011 0.012 0.013 0.014 0.016 0.017 0.018 0.019 0.020 0.022 0.023 0.02411.25 0.007 0.008 0.009 0.011 0.012 0.014 0.015 0.016 0.018 0.019 0.020 0.022 0.023 0.024 0.026 0.02712.5 0.008 0.009 0.011 0.012 0.014 0.015 0.017 0.018 0.020 0.021 0.023 0.024 0.026 0.027 0.029 0.03013.75 0.008 0.010 0.012 0.013 0.015 0.017 0.018 0.020 0.021 0.023 0.025 0.026 0.028 0.030 0.031 0.03315 0.009 0.011 0.013 0.014 0.016 0.018 0.020 0.022 0.023 0.025 0.027 0.029 0.031 0.032 0.034 0.03616.25 0.010 0.012 0.014 0.016 0.018 0.020 0.021 0.023 0.025 0.027 0.029 0.031 0.033 0.035 0.037 0.03917.5 0.011 0.013 0.015 0.017 0.019 0.021 0.023 0.025 0.027 0.029 0.032 0.034 0.036 0.038 0.040 0.04218.75 0.011 0.014 0.016 0.018 0.020 0.023 0.025 0.027 0.029 0.032 0.034 0.036 0.038 0.041 0.043 0.04520 0.012 0.014 0.017 0.019 0.022 0.024 0.026 0.029 0.031 0.034 0.036 0.038 0.041 0.043 0.046 0.04821.25 0.013 0.015 0.018 0.020 0.023 0.026 0.028 0.031 0.033 0.036 0.038 0.041 0.043 0.046 0.048 0.05122.5 0.014 0.016 0.019 0.022 0.024 0.027 0.030 0.032 0.035 0.038 0.041 0.043 0.046 0.049 0.051 0.05423.75 0.014 0.017 0.020 0.023 0.026 0.029 0.031 0.034 0.037 0.040 0.043 0.046 0.048 0.051 0.054 0.05725 0.015 0.018 0.021 0.024 0.027 0.030 0.033 0.036 0.039 0.042 0.045 0.048 0.051 0.054 0.057 0.06027.5 0.017 0.020 0.023 0.026 0.030 0.033 0.036 0.040 0.043 0.046 0.050 0.053 0.056 0.059 0.063 0.06630 0.018 0.022 0.025 0.029 0.032 0.036 0.040 0.043 0.047 0.050 0.054 0.058 0.061 0.065 0.068 0.07232.5 0.020 0.023 0.027 0.031 0.035 0.039 0.043 0.047 0.051 0.055 0.059 0.062 0.066 0.070 0.074 0.07835 0.021 0.025 0.029 0.034 0.038 0.042 0.046 0.050 0.055 0.059 0.063 0.067 0.071 0.076 0.080 0.08437.5 0.023 0.027 0.032 0.036 0.041 0.045 0.050 0.054 0.059 0.063 0.068 0.072 0.077 0.081 0.086 0.09040 0.024 0.029 0.034 0.038 0.043 0.048 0.053 0.058 0.062 0.067 0.072 0.077 0.082 0.086 0.091 0.09642.5 0.026 0.031 0.036 0.041 0.046 0.051 0.056 0.061 0.066 0.071 0.077 0.082 0.087 0.092 0.097 0.102

The shaded areas indicate the highest infusion rate which is possible with a 3 ml syringe change everythree days.

Table 1-3 provides guidance for subcutaneous infusion delivery rates of Trepulmix 5 mg/ml forpatients of different body weights corresponding to doses of up to 80 ng/kg/min.

Table 1-3:

Infusion rate setting of subcutaneous pump (ml/h) for Trepulmix 5 mg/ml

Patient weight (kg)

Dose(ng/kg/min) 35 40 45 50 55 60 65 70 75 80 85 90 95 10010 0.004 0.005 0.005 0.006 0.007 0.007 0.008 0.008 0.009 0.010 0.010 0.011 0.011 0.01212.5 0.005 0.006 0.007 0.008 0.008 0.009 0.010 0.011 0.011 0.012 0.013 0.014 0.014 0.01515 0.006 0.007 0.008 0.009 0.010 0.011 0.012 0.013 0.014 0.014 0.015 0.016 0.017 0.01817.5 0.007 0.008 0.009 0.011 0.012 0.013 0.014 0.015 0.016 0.017 0.018 0.019 0.020 0.02120 0.008 0.010 0.011 0.012 0.013 0.014 0.016 0.017 0.018 0.019 0.020 0.022 0.023 0.02422.5 0.009 0.011 0.012 0.014 0.015 0.016 0.018 0.019 0.020 0.022 0.023 0.024 0.026 0.02725 0.011 0.012 0.014 0.015 0.017 0.018 0.020 0.021 0.023 0.024 0.026 0.027 0.029 0.03027.5 0.012 0.013 0.015 0.017 0.018 0.020 0.021 0.023 0.025 0.026 0.028 0.030 0.031 0.03330 0.013 0.014 0.016 0.018 0.020 0.022 0.023 0.025 0.027 0.029 0.031 0.032 0.034 0.03632.5 0.014 0.016 0.018 0.020 0.021 0.023 0.025 0.027 0.029 0.031 0.033 0.035 0.037 0.03935 0.015 0.017 0.019 0.021 0.023 0.025 0.027 0.029 0.032 0.034 0.036 0.038 0.040 0.04237.5 0.016 0.018 0.020 0.023 0.025 0.027 0.029 0.032 0.034 0.036 0.038 0.041 0.043 0.04540 0.017 0.019 0.022 0.024 0.026 0.029 0.031 0.034 0.036 0.038 0.041 0.043 0.046 0.04842.5 0.018 0.020 0.023 0.026 0.028 0.031 0.033 0.036 0.038 0.041 0.043 0.046 0.048 0.05145 0.019 0.022 0.024 0.027 0.030 0.032 0.035 0.038 0.041 0.043 0.046 0.049 0.051 0.05447.5 0.020 0.023 0.026 0.029 0.031 0.034 0.037 0.040 0.043 0.046 0.048 0.051 0.054 0.05750 0.021 0.024 0.027 0.030 0.033 0.036 0.039 0.042 0.045 0.048 0.051 0.054 0.057 0.06055 0.023 0.026 0.030 0.033 0.036 0.040 0.043 0.046 0.050 0.053 0.056 0.059 0.063 0.06660 0.025 0.029 0.032 0.036 0.040 0.043 0.047 0.050 0.054 0.058 0.061 0.065 0.068 0.07265 0.027 0.031 0.035 0.039 0.043 0.047 0.051 0.055 0.059 0.062 0.066 0.070 0.074 0.07870 0.029 0.034 0.038 0.042 0.046 0.050 0.055 0.059 0.063 0.067 0.071 0.076 0.080 0.08475 0.032 0.036 0.041 0.045 0.050 0.054 0.059 0.063 0.068 0.072 0.077 0.081 0.086 0.09080 0.034 0.038 0.043 0.048 0.053 0.058 0.062 0.067 0.072 0.077 0.082 0.086 0.091 0.096

The shaded areas indicate the highest infusion rate which is possible with a 3 ml syringe change everythree days.

Table 1-4 provides guidance for subcutaneous infusion delivery rates of Trepulmix 10 mg/ml forpatients of different body weights corresponding to doses of up to 155 ng/kg/min.

Table 1-4:

Infusion rate setting of subcutaneous pump (ml/h) for Trepulmix 10 mg/ml

Patient weight (kg)

Dose(ng/kg/min) 35 40 45 50 55 60 65 70 75 80 85 90 95 10050 0.011 0.012 0.014 0.015 0.017 0.018 0.020 0.021 0.023 0.024 0.026 0.027 0.029 0.03055 0.012 0.013 0.015 0.017 0.018 0.020 0.021 0.023 0.025 0.026 0.028 0.030 0.031 0.03360 0.013 0.014 0.016 0.018 0.020 0.022 0.023 0.025 0.027 0.029 0.031 0.032 0.034 0.03665 0.014 0.016 0.018 0.020 0.021 0.023 0.025 0.027 0.029 0.031 0.033 0.035 0.037 0.03970 0.015 0.017 0.019 0.021 0.023 0.025 0.027 0.029 0.032 0.034 0.036 0.038 0.040 0.04275 0.016 0.018 0.020 0.023 0.025 0.027 0.029 0.032 0.034 0.036 0.038 0.041 0.043 0.04580 0.017 0.019 0.022 0.024 0.026 0.029 0.031 0.034 0.036 0.038 0.041 0.043 0.046 0.04885 0.018 0.020 0.023 0.026 0.028 0.031 0.033 0.036 0.038 0.041 0.043 0.046 0.048 0.05190 0.019 0.022 0.024 0.027 0.030 0.032 0.035 0.038 0.041 0.043 0.046 0.049 0.051 0.05495 0.020 0.023 0.026 0.029 0.031 0.034 0.037 0.040 0.043 0.046 0.048 0.051 0.054 0.057100 0.021 0.024 0.027 0.030 0.033 0.036 0.039 0.042 0.045 0.048 0.051 0.054 0.057 0.060105 0.022 0.025 0.028 0.032 0.035 0.038 0.041 0.044 0.047 0.050 0.054 0.057 0.060 0.063110 0.023 0.026 0.030 0.033 0.036 0.040 0.043 0.046 0.050 0.053 0.056 0.059 0.063 0.066115 0.024 0.028 0.031 0.035 0.038 0.041 0.045 0.048 0.052 0.055 0.059 0.062 0.066 0.069120 0.025 0.029 0.032 0.036 0.040 0.043 0.047 0.050 0.054 0.058 0.061 0.065 0.068 0.072125 0.026 0.030 0.034 0.038 0.041 0.045 0.049 0.053 0.056 0.060 0.064 0.068 0.071 0.075130 0.027 0.031 0.035 0.039 0.043 0.047 0.051 0.055 0.059 0.062 0.066 0.070 0.074 0.078135 0.028 0.032 0.036 0.041 0.045 0.049 0.053 0.057 0.061 0.065 0.069 0.073 0.077 0.081140 0.029 0.034 0.038 0.042 0.046 0.050 0.055 0.059 0.063 0.067 0.071 0.076 0.080 0.084145 0.030 0.035 0.039 0.044 0.048 0.052 0.057 0.061 0.065 0.070 0.074 0.078 0.083 0.087150 0.032 0.036 0.041 0.045 0.050 0.054 0.059 0.063 0.068 0.072 0.077 0.081 0.086 0.090155 0.033 0.037 0.042 0.047 0.051 0.056 0.060 0.065 0.070 0.074 0.079 0.084 0.088 0.093

Shaded areas indicate the highest infusion rate supported by a 3 ml syringe change every three days.

* Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

* Pulmonary veno-occlusive disease.

* Severe decompensated left heart failure.

* Severe hepatic impairment (Child-Pugh Class C).

* Active gastrointestinal ulcer, intracranial haemorrhage, gastrointestinal injury or othergastrointestinal bleeding.

* Congenital or acquired valvular defects with clinically relevant myocardial dysfunctionnot related to pulmonary hypertension.

* Severe coronary heart disease or unstable angina

* Myocardial infarction within the last six months

* Severe arrhythmias

* Cerebrovascular events (e.g. transient ischaemic attack, stroke) within the last threemonths.

* Co-administration with other prostanoids

General therapy

The decision to initiate therapy with treprostinil should take into consideration the high probabilitythat continuous infusion will have to be continued for a prolonged period. Thus the patient's ability toaccept and to be responsible for an indwelling catheter and infusion device should be carefullyconsidered. The clinical team responsible for the therapy must ensure that the patient is fully trainedand competent to use the chosen infusion device (see section 4.2).

Treprostinil is a potent pulmonary and systemic vasodilator. In subjects presenting with low systemicarterial pressure, treprostinil treatment may increase the risk of systemic hypotension. Treatment is notrecommended for patients with systolic arterial pressure of less than 85 mmHg.

It is recommended to monitor systemic blood pressure and heart rate during any change in dose withinstructions to stop the infusion if symptoms of hypotension develop, or a systolic blood pressure of85 mmHg or lower is detected.

If a patient develops pulmonary oedema while on treprostinil, the possibility of a concomitantpulmonary veno-occlusive disease should be considered. The treatment should be stopped aspulmonary veno-occlusive disease is a contraindication for therapy with treprostinil (see section 4.3).

Caution is advised in situations where treprostinil may increase the risk of bleeding by inhibitingplatelet aggregation (see section 4.5 and 4.8).

Abrupt withdrawal or sudden marked reductions in the dose of treprostinil may cause a rebound inpulmonary hypertension (see section 4.2).

Patients with hepatic and renal impairment should be dosed cautiously (see section 4.2).

As treprostinil and its metabolites are excreted mainly through the urinary route, caution isrecommended when treating patients with renal impairment in order to prevent deleteriousconsequences related to the possible increase of systemic exposure (see section 4.2).

Concomitant administration of cytochrome P450 (CYP2C8) enzyme inhibitors (as gemfibrozil) maylead to increased exposure (both Cmax and AUC) to treprostinil. With an increased exposure there is alikelihood of a higher incidence of adverse events associated with the administration of treprostinil.

Therefore, a dose reduction should be considered (see section 4.5).

Concomitant administration of CYP2C8 enzyme inducers (for example rifampicin) may result in adecreased exposure to treprostinil. At a reduced exposure, it is likely to have decreased clinicalefficacy. Therefore, a higher dose of treprostinil is to be considered (see section 4.5).

Trepulmix 1 mg/ml solution for infusion

This medicinal product contains 36.8 mg sodium per 10 ml vial of 1 mg/ml, equivalent to 1.8% of the

WHO recommended maximum daily intake of 2 g sodium for an adult.

Trepulmix 2.5 mg/ml solution for infusion

This medicinal product contains 37.3 mg mg sodium per 10 ml vial of 2.5 mg/ml, equivalent to 1.9%of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Trepulmix 5 mg/ml solution for infusion

This medicinal product contains 39.1 mg sodium per 10 ml vial of 5 mg/ml, equivalent to 2.0% of the

WHO recommended maximum daily intake of 2 g sodium for an adult.

Trepulmix 10 mg/ml solution for infusion

This medicinal product contains 37.4 mg sodium per 10 ml vial of 10 mg/ml, equivalent to 1.9% of the

WHO recommended maximum daily intake of 2 g sodium for an adult.

To be taken into consideration by patients on a controlled sodium diet.

Concomitant administration with diuretics, antihypertensive agents, or other vasodilators

Concomitant administration of treprostinil with diuretics, antihypertensive agents or other vasodilatorsincreases the risk of systemic hypotension.

Concomitant administration with platelet aggregation inhibitors, including NSAIDs and anticoagulants

Treprostinil may inhibit platelet function. Concomitant administration of treprostinil with plateletaggregation inhibitors, including NSAIDs, nitric oxide donors or anticoagulants may increase the riskof bleeding. Surveillance of patients taking anticoagulants should be closely maintained. Theconcomitant use of other platelet inhibitors should be avoided in patients taking anticoagulants.

Concomitant administration with cytochrome P450 (CYP2C8) enzyme inducers/inhibitors

Gemfibrozil and other CYP2C8 inhibitors

Pharmacokinetic studies in humans with oral treprostinil diolamine indicated that the concomitantadministration of cytochrome P450 (CYP2C8) enzyme inhibitor gemfibrozil doubles the exposure(both Cmax and AUC) to treprostinil. In case a CYP2C8 inhibitor (e.g. gemfibrozil, trimethoprim anddeferasirox) is added to or omitted from the patient’s treatment after the titration phase, a doseadjustment of treprostinil has to be considered.

Rifampicin and other CYP2C8 inducers

Pharmacokinetic studies in humans with oral treprostinil diolamine indicated that the concomitantadministration of CYP2C8 enzyme inducer rifampicin resulted in a reduced (by about 20%) exposureto treprostinil. In case rifampicin is added to or omitted from the patient’s treatment after the titrationphase, a dose adjustment of treprostinil has to be considered.

Also other CYP2C8 inducers (e.g. phenytoin, carbamazepine, phenobarbital and St. John's Wort) maylead to reduced exposure to treprostinil. In case a CYP2C8 inhibitor is added to or omitted from thepatient’s treatment after the titration phase, a dose adjustment of treprostinil has to be considered.

Concomitant administration with bosentan

In a pharmacokinetic study in humans, in which bosentan (250 mg/day) and treprostinil diolamine(oral dose of 2 mg/day) were administered concomitantly, no pharmacokinetic interaction betweentreprostinil and bosentan was observed.

Concomitant administration with sildenafil

In a pharmacokinetic study in humans, in which sildenafil (60mg/day) and treprostinil diolamine (oraldose of 2 mg/day) were administered concomitantly, no pharmacokinetic interaction betweentreprostinil and sildenafil was observed.

There are no or limited amount of data from the use of treprostinil in pregnant women. Animal studiesare insufficient with respect to effects on pregnancy (see section 5.3). Treprostinil should only be usedduring pregnancy if the potential benefit to the mother justifies the potential risk to the foetus.

Contraception is recommended during treprostinil treatment.

It is not known whether treprostinil is excreted in human milk. Breastfeeding women takingtreprostinil should be advised to discontinue breastfeeding.

Trepulmix has minor influence on the ability to drive and use machines at the initiation of treatment ordose adjustments. They may be accompanied by undesirable effects such as symptomatic systemichypotension or dizziness which may impair ability to drive and operate machinery.

In addition to local effects resulting from the administration of treprostinil by subcutaneous infusionsuch as infusion site pain and infusion site reaction, adverse reactions with treprostinil are related tothe pharmacological properties of prostacyclins.

The adverse reactions are presented as MedDRA preferred terms under the MedDRA system organclass. The incidence of the adverse reactions below are expressed according to the followingcategories: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare(≥1/10 000 to <1/1 000); very rare (<1/10 000).

System organ class Adverse reaction Incidence

Nervous system disorders Headache Very common

Dizziness Common

Eye disorders Eyelid oedema Uncommon

Cardiac disorders Vasodilatation Very common

Hypotension Common

Gastrointestinal disorders Diarrhoea Very common

Nausea Very common

Dyspepsia Uncommon

Vomiting Uncommon

Skin and subcutaneous tissuedisorders Rash Common

Pruritus Uncommon

Exanthema Uncommon

Musculoskeletal, connectivetissue disorders Jaw pain Very common

Myalgia, arthralgia Common

Pain in extremities Common

Back pain Uncommon

General disorders and Infusion site pain, infusion siteadministration site conditions reaction, bleeding or haematoma Very common

Infusion site abscess Common

Infusion site infection Common

Oedema Common

Flushing Common

Decreased appetite Uncommon

Fatigue Uncommon

Bleeding events

Due to its effects on platelet aggregation, treprostinil may increase the risk of bleeding, as observed byan increased incidence of epistaxis and gastrointestinal (GI) bleeding (including GI haemorrhage,rectal haemorrhage, gum haemorrhage and melaena) in controlled clinical trials in PAH.

Events observed during clinical practice:

In addition to adverse reactions reported from clinical trials in PAH patients, the following events havebeen identified during post-approval use of treprostinil in other indications. Because they are reportedvoluntarily from a population of unknown size, estimates of frequency cannot be made. The followingevents were reported:, thrombocytopenia, bone pain.

In addition, generalised rashes, sometimes macular or papular in nature, and cellulitis have beeninfrequently reported.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V..

Symptoms of overdose with treprostinil include flushing, headache, hypotension, nausea, vomiting,and diarrhoea. Patients experiencing symptoms of overdose should, after consultation with theirphysician, immediately reduce their dose of treprostinil depending on the severity of the symptomsuntil the symptoms of overdose have resolved. Dosing should be recommenced with caution undermedical control and patients monitored closely for recurrence of unwanted symptoms.

No antidote is known.

Pharmacotherapeutic group: Antithrombotic agents, platelet aggregation inhibitors excl. heparin

ATC code: B01AC21

Treprostinil is a prostacyclin analogue.

It exerts a direct vasodilation effect on the pulmonary and systemic arterial circulation and, inhibitsplatelet aggregation.

In a randomised, multi-centre, controlled clinical trial, a total of 105 male (53.3%) and female (46.7%)adult patients with inoperable CTEPH or persistent or recurrent CTEPH after pulmonaryendarterectomy (18-88 years of age, mean 64 years) were treated. Patients were required to have

CTEPH classified as severe, as defined by an un-encouraged six-minute walk test (6MWT) of between150 and 400 meters and a classification in the WHO/NYHA functional class III or IV. Patients weredivided into two treprostinil treatment groups (53 high dose and 52 low dose patients, treated withsubcutaneous infusion for a total of 24 weeks) as follows. In the high dose group, patients wereadministered a subcutaneous dose via infusion pump that increased from approximately 1 to a targetdose of approximately 30 ng/kg/min for the first 12 weeks, followed by 12 weeks of stable perfusion;in the low dose group, the target dose was approximately 3 ng/kg/min following the same schedule.

The primary efficacy analysis was based on the individual difference between the 6MWT data atbaseline and after 24 weeks. Treprostinil improved the six-minute walk distance (6MWT, six-minutewalk test: baseline vs. 24 weeks of treatment) by a mean of 45.43 m in the high dose group versus 3.83m in the low dose group (p < 0.05, ANCOVA). Exploratory secondary efficacy (low vs. high)measures, after 24 weeks of treatment, showed -significant improvements in New York Heart

Association functional (NYHA) class, haemodynamic parameters (mean pulmonary vascularresistance, mean pulmonary arterial pressure, mean cardiac output, and mean cardiac index) andmedian pro-BNP (brain natriuretic peptide values) in favor of the high dose group. No significantdifferences between the two test groups in the number of patients showing a 'clinical worsening',defined as a reduction of 6MWD of 20% compared to baseline, worsening of NYHA functional classand/or hospitalisation due to CTEPH with the need of additional pulmonary hypertension specifictreatment, were observed. High dose treprostinil showed no significant changes in the Borg Dyspnoea

Score (measured during the 6MWT), or the summed Quality of Life score as assessed by the

Minnesota Living with Heart Failure Questionnaire.

In humans, steady-state plasma concentrations are usually achieved within 15 to 18 hours of theinitiation of either subcutaneous or intravenous infusion of treprostinil. Steady-state plasmaconcentrations of treprostinil are dose-proportional at infusion rates of 2.5 up to 125 ng/kg/min.

The mean apparent elimination half-life following subcutaneous administration ranged from 1.32 to1.42 hours after infusions over 6 hours, pct. 4.61 hours after infusions over 72 hours, and 2.93 hours afterinfusions lasting at least three weeks. The mean volume of distribution for treprostinil ranged from1.11 to 1.22 l/kg, and plasma clearance ranged from 586.2 to 646.9 ml/kg/h. Clearance is lower inobese subjects (body mass index (BMI) > 30 kg/m2).

In a seven-day chronic pharmacokinetic study in 14 healthy volunteers with treprostinil doses rangingfrom 2.5 to 15 ng/kg/min administered by subcutaneous infusion, steady state plasma treprostinilconcentrations reached peak levels twice (at 1 a.m. and 10 a.m. respectively) and trough levels twice(at 7 a.m. and 4 p.m. respectively). The peak concentrations were approximately 20% to 30% higherthan the trough concentrations.

In a study conducted on healthy volunteers using [14C] radioactive treprostinil, 78.6% and 13.4% ofthe subcutaneous radioactive dose were recovered in the urine and faeces respectively over a period of224 hours. No single major metabolite was observed. Five metabolites were detected in the urine,ranging from 10.2% to 15.5% of the dose administered. These five metabolites accounted for acombined total of 64.4%. Three are products of oxidation of the 3-hydroxyloctyl side chain, one is aglucuroconjugated derivative (treprostinil glucuronide) and one is unidentified. Only 3.7% of the dosewas recovered in the urine as unchanged parent drug.

An in vitro study demonstrated no inhibitory potential of treprostinil to human hepatic microsomalcytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A).

Moreover, administration of treprostinil had no inducing effect on hepatic microsomal protein, totalcytochrome (CYP) P 450 content or on the activities of the isoenzymes CYP1A, CYP2B and CYP3A.

In patients with portopulmonary hypertension and mild (n=4) or moderate (n=5) hepatic insufficiency,treprostinil at a subcutaneous dose of 10 ng/kg/min for 150 minutes had an AUC 0-24 h that wasincreased 260 % and 510 %, respectively, compared to healthy subjects. Clearance in patients withhepatic insufficiency was reduced by up to 80% compared to healthy adults (see section 4.2).

In a multivariate analysis of pooled studies, patients in the age group ≥ 65 years had a small reductionin plasma clearance of treprostinil. However, most publications regarded either healthy volunteers orpatient with PAH. CTEPH patients were rarely described. Age stratification was not performed in anypublication. As only few studies reported on PK parameters but none reported both on CTEPHindication and PK data, no information is available on the pharmacokinetics of treprostinil in elderlypatients.

Preclinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, and toxicity to reproduction.

In 13 and 26 week studies continuous subcutaneous infusions of treprostinil sodium caused infusionsite reactions in rats and dogs (oedema/erythema, masses/swellings, pain/sensitivity to touch). In dogssevere clinical effects (hypoactivity, emesis, loose stool and infusion site oedema) and death(associated with intestinal intussusceptions and rectal prolapse) were observed in animals administered≥ 300ng/kg/min. Mean steady state plasma treprostinil levels of 7.85 ng/ml were measured in theseanimals. Plasma levels of this order may be achieved in humans treated with treprostinil infusions at> 50ng/kg/min.

As a continuously sufficient exposure to treprostinil has not been proven for any dose tested in thereproductive studies in rats, these studies might be insufficient regarding possible effects on fertility,prenatal and postnatal development.

No long-term animal studies have been performed to evaluate treprostinil’s carcinogenic potential.

Sodium citrate

Hydrochloric acid

Metacresol

Sodium hydroxide

Sodium chloride

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

Unopened vial3 years.

After first opening30 days.

During use with continuous subcutaneous infusion

Chemical, physical and microbial in-use stability of a single container (syringe) of undiluted

Trepulmix administered subcutaneously has been demonstrated for 72 h at 37 °C.

This medicinal product does not require any special storage conditions.

For storage conditions after first opening of the medicinal product, see section 6.3.

Trepulmix 1 mg/ml solution for infusion10 ml type I clear glass vial sealed with a rubber teflon- coated stopper and fitted with a yellow cap.

Trepulmix 2.5 mg/ml solution for infusion10 ml type I clear glass vial sealed with a rubber teflon- coated stopper and fitted with a blue cap.

Trepulmix 5 mg/ml solution for infusion10 ml type I clear glass vial sealed with a rubber teflon- coated stopper and fitted with a green cap.

Trepulmix 10 mg/ml solution for infusion10 ml type I clear glass vial sealed with a rubber teflon- coated stopper and fitted with a red cap.

Each carton contains one vial.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

SciPharm Sàrl7, Fausermillen

L-6689 Mertert

Luxembourg

EU/1/19/1419/001

EU/1/19/1419/002

EU/1/19/1419/003

EU/1/19/1419/004

Date of first authorisation: 03 April 2020

Date of latest renewal: 13 December 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.